This invention relates to methods for treating schizophrenia and/or reducing the symptoms thereof.
Schizophrenia is a relatively intractable mental disorder. Although there can be, and often are, psycho-social aspects to the disease, it is well understood to have a clear physiological component. Many medical and psychopharmaceutical treatments have been used in this disorder, with varying degrees of success. However, as yet, there is no true understanding of the cause of the underlying biochemical nature of the disorder, nor any satisfactory long term treatment for it.
The manifestations of schizophrenia are numerous and often contradictory. The symptoms can be generally grouped into three groups; positive, or expressive symptomatology; negative, or deficit, symptomatology; and social symptomatology. Many schizophrenic patients are partially or completely refractory to standard anti-psychotic drug treatments. Currently, there are no adequate treatments for some symptoms of the disorder, especially negative symptoms which include amotivation, anhedonia, alogia, anergia, and affective impairment. These symptoms have profound effects on psychosocial function and rehabilitation potential.
Standard antipsychotic treatments in use today include the use of neuroleptics, which include such drugs as haloperidol and chlorpromazine. These medications generally act through blocking the dopamine D.sub.2 receptor. In particular, these medications are thought to work through the selective reduction of dopaminergic tone in one or more of the four major brain dopamine tracts, i.e., the mesolimbic, the mesofrontal, the nigrostriatial and the tuberofundibular tracts. The mesolimbic tract is thought to be involved in the positive symptoms of schizophrenia; thus, reduction by antipsychotic medications of dopamine tone in this tract is thought to be involved in the therapeutic mechanism of those agents.
However, recent work by Weinberger (Arch. Gen. Psychiatry, XX, 1987) and others suggests that mesofrontal dopamine deficits may be implicated in negative schizophrenic symptoms. Consistent with this, most schizophrenics experience minimal negative symptom improvement or even worsening with standard neuroleptic treatment. Hence, the complex pathophysiology of schizophrenia includes both increased dopamine tone (in mesolimbic dopamine tracts) and decreased dopamine tone (in mesofrontal dopamine tracts). The treatment of schizophrenia with standard neuroleptics results in global reductions of dopamine neuron function in all dopamine tracts and thus may be responsible for the ineffective or deleterious responses of negative schizophrenic symptoms to neuroleptics.
Mazindol (5-hydroxy-5-p-chlorophenyl-2,3-dihydro-5H-imidazo[2,1-a]isoindole) is a long-acting agent that blocks dopamine reuptake at the dopamine transporter site located on the presynaptic neuron, and is in widespread clinical use as an anorectic. Its minimal side effects include restlessness and insomnia. Because of its cocaine-like dopamine reuptake inhibition, it is of use in both Parkinson's disease and narcolepsy. Although Parkinson's patients are notoriously sensitive to side effects, mazindol is a remarkably well tolerated drug. Out of twelve patients in a recent pilot study of mazindol for Parkinsonism, only two reported even mild side effects. (Delwaid, P. J., et al., "Mazindol in the treatment of Parkinson's disease," Arch Neurol. 40, 788-790, 1983.) In a recent report, unexpectedly, when given blindly to drug abusers, the oral clinical dose of mazindol was mildly dysphoric and free of abuse potential (Chait, et al., "Reinforcing and Subjective Effects of Several Anorectics in Normal Human Volunteers," J. Pharmaceutical Exp. Ther. 242, 777-83, 1987). However, prior to the present invention, mazindol was tested in schizophrenics (Krumholz, W.V. et al., "Clinical evaluation of mazindol in chronic schizophrenics," Curr. Therapeutic Res. 12, 609-610, 1970), and found to lead to an increase in schizophrenic symptomatology, to cause at the high doses which were administered enhancement of peripheral sympathetic activity, and therefore, not to be indicated in the treatment of chronic schizophrenia.